The Role of Alzheimer's-associated Abeta in POD and POCD

描述(申请人提供)：术后精神障碍(POD)和术后认知功能障碍(POCD)是老年人手术后最常见的两种并发症，极大地增加了围手术期的发病率、死亡率和医疗费用。然而，目前POD和POCD都是临床现象，其神经发病机制很大程度上还不清楚。这一认识上的差距阻碍了旨在解决POD和POCD潜在机制的有针对性的预防和治疗战略的制定。我们的初步研究表明，术前即刻脑脊液中高水平的IL-6水平和低水平的A2水平与POD和术后记忆障碍有关，这与我们的中枢假说2-淀粉样蛋白(A2)积聚和神经炎症(如小胶质细胞激活和脑内细胞因子积聚)与认知功能障碍有关，这表明脑内高水平的A2和细胞因子可能在POD和POCD的神经发病机制中发挥作用。因此，本研究旨在通过检验一种假说来确定POD和POCD的神经发病机制，该假说认为大脑中高水平的A2和IL-6代表围手术期应激下脑组织脆弱性的标志，从而导致POD和POCD。我们将通过床边认知测试和床边生化分析来实现三个具体目标：(1)研究术前脑脊液A2和IL-6水平与腰麻下常规全髋关节置换术后第1、2和3天POD的相关性，并在腰麻下收集脑脊液，从而不会增加参与者的风险；(2)在同一人群中，确定术前脑脊液A2和IL-6水平与术后7天、3个月和1年POCD的相关性；(3)进行匹兹堡化合物B正电子发射断层扫描测定脑淀粉样蛋白含量的可行性研究及术前、术后即刻脊髓导管采集脑脊液的可行性研究。我们将使用有效和标准化的方法评估POD和POCD，并用ELISA法测定脑脊液A2、IL-6和皮质醇水平。建议的项目将提供有关POD和POCD神经发病机制的重要信息，因此具有很高的创新性和重要意义。预期的结果将为POD和POCD的针对性预防和治疗策略的设计提供信息，因此有可能最终为老年人带来更好的麻醉和手术护理。我们的建议符合国家老龄研究所的主要使命，即减轻老年人的疾病和残疾负担。 公共卫生相关性：术后精神障碍(POD)和术后认知功能障碍(POCD)增加了围手术期的发病率、死亡率和医疗费用。然而，POD和POCD的神经发病机制在很大程度上还不清楚。这项拟议的研究将使用临床认知测试和生化分析来确定POD和POCD在人类中的神经发病机制，最终将为患者，特别是老年患者带来更好的麻醉和手术护理。

DESCRIPTION (provided by applicant): Post-operative delirium (POD) and Post-operative cognitive dysfunction (POCD) are the two most common post-operative complications in older adults, and substantially increase peri-operative morbidity, mortality and cost of medical care. However, at present time, both POD and POCD are clinical phenomena and their neuropathogeneisis is largely unknown. This gap in knowledge has impeded development of targeted prevention and treatment strategies designed to address the underlying mechanisms of POD and POCD. Consistent with our central hypotheses that 2-Amyloid protein (A2) accumulation and neuroinflammation (e.g., microglia activation and brain cytokine accumulation) are linked with cognitive dysfunction and delirium, our preliminary studies have shown that high IL-6 levels and low A2 levels in the immediate pre-operative cerebrospinal fluid (CSF) are associated with POD and post-operative memory impairment, which suggest that high levels of A2 and cytokine in the brain may play a role in POD and POCD neuropathogenesis. Thus, the proposed research is aimed at determining the neuropathogenesis of POD and POCD by testing a hypothesis that high levels of A2 and IL-6 in the brain represent markers of brain vulnerability under peri-operative stress, leading to POD and POCD. We will employ bed-side cognitive tests and bench-side biochemistry analysis to accomplish three Specific Aims: (1) to investigate the association of pre-operative CSF A2 and IL-6 levels with POD measured 1, 2 and 3 days after scheduled total hip and knee replacement surgery conducted under spinal anesthesia, the CSF will be collected when spinal anesthesia is performed and therefore poses no added risk to the participants; (2) to determine the association of pre-operative CSF A2 and IL-6 levels with POCD measured 7 days, 3 months, and 1 year after surgery in the same population; (3) to perform feasibility studies of using positron emission tomographic imaging with Pittsburgh Compound B to measure brain amyloid amount and of using spinal catheter to collect immediate pre- and post-operative CSF. We will assess POD and POCD using validated and standardized methods, and measure CSF A2, IL-6 and cortisol levels with ELISA. The proposed project will provide important information regarding the neuropathogenesis of POD and POCD, and therefore is highly innovative and significant. The anticipated results will inform the design of targeted prevention and treatment strategies for POD and POCD and therefore have the potential to ultimately lead to better anesthesia and surgery care for older adults. Our proposal meets with the major mission of the National Institute of Aging to reduce the burdens of illness and disability in the elderly. PUBLIC HEALTH RELEVANCE: Post-operative delirium (POD) and Post-operative cognitive dysfunction (POCD) increase peri-operative morbidity, mortality and cost of medical care. However, the neuropathogeneisis of POD and POCD is largely unknown. The proposed research will employ both clinical cognitive tests and biochemistry analysis to determine the neuropathogenesis of POD and POCD in humans, which would ultimately lead to a better anesthesia and surgery care for patients, especially geriatric patients.